The present invention relates to the use of strains of Parapoxvirus ovis as immunotherapeutic agents for immunodeficiencies of an infectious or non-infectious nature, and to the use of strains of Parapoxvirus ovis for treating tumour diseases and viral infections and diseases which accompany such infections, and the use of strains of Parapoxvirus ovis for producing medicaments for use in humans and animals.
The present invention furthermore relates to the use of strains of Parapoxvirus ovis, and of medicinal forms prepared therefrom, as immunotherapeutic agents or immunoprophylactic agents in stress metaphylaxis for preventing or averting infectious diseases following stress (e.g. operations); to their use in infection prophylaxis, for preventing or averting infectious diseases by means of administration prior to operations or interventions (e.g. before implantation of prostheses or before dental interventions), to their use in infection metaphylaxis or the therapy of acute or chronic viral infections, for example of the respiratory tract, of papilloma virus infections, of infection with herpesviruses, of HIV infection, and of viral infection of internal organs such as infection with hepatitis viruses, to their use in wound healing, in order to accelerate wound healing processes, and to their use for supporting the healing of wounds which only heal poorly or do not heal at all (e.g. ulcer of the leg), to their use for diseases such as multiple sclerosis, asthma, warts and other neoformations of the skin, to their use for diseases of the spectrum of allergic diseases, to their use for preventing the onset of systemic allergies, and to their use for topical allergies and to their use for improving wellbeing, for example in elderly patients, with the strains of Parapoxvirus ovis which are used within the context of the invention being the strains NZ2, NZ-7, NZ-10 and orf-11.
It is also possible to use descendants of these strains which have been obtained by passaging and/or adaptation to particular cells, for example WI-38, MRC-5 or Vero cells, or parts or fragments of viruses from these strains or of these descendants. Parts are to be understood as meaning genomic or subgenomic fragments which are expressed with the aid of suitable vectors, for example vaccinia, in suitable systems, for example fibroblast cell cultures. Fragments are understood as being the fractions, which are obtained by biochemical purification, for example by means of chromatography, of particles which have been physically disrupted, for example by means of ultrasonication.
The present invention furthermore relates to the use of the said strains of Parapoxvirus ovis for producing medicaments and pharmaceutical preparations. In addition to this, the invention relates to the use of the said strains of Parapoxvirus ovis, in combination with other remedies, for producing medicaments and pharmaceutical preparations for antiviral therapy or cancer therapy.
It is known that latent and chronic persistent viral infections can be activated or reactivated by an immunosuppression, or, conversely, that the immune system suppresses the acute disease which can be induced by a virus which is latent (e.g. a latent herpesvirus infection recurs in association with immunosuppression: labial blisters in association with stress or cortisone administration). It is furthermore known that chronically persistent and latent viral infections are difficult or even impossible to treat using conventional antiviral substances with a low molecular weight basis.
A reason for this can be the absence of viral enzymic activity in connection with such infections (for example the absence of any viral polymerase activity which firstly has to incorporate a nucleosidic inhibitor into the viral nucleic acid so that this inhibitor can, for example, give rise to chain termination in the viral DNA; for example the absence of any viral thymidine kinase activity, which firstly has, for example, to phosphorylate an antiviral compound so that this compound can become active), or else the lack of any recognition, by the immune system of the host, of infected or degenerate cells, for example cancer cells, or of viral antigens.
It is also known that, in association with chronically persistent viral infections, a superinfection with another virus can give rise to antiviral effects which are directed against the chronically persistent virus1). The authors1) were able to demonstrate the dependence of this effect on interferons, such as IFN-xcex3 and TNF-xcex1, which are secreted by T cells, natural killer cells and macrophages.
The results obtained by these authors confirmed another, earlier study which demonstrated that Class I-restricted cytotoxic T cells were able to inhibit hepatocellular HBV gene expression in HBV-transgenic mice, that this process took place without any destruction of the liver cells, and that the process was elicited by TNF-xcex1 and IFN-xcex32).
A product for inducing xe2x80x9cparaspecific immunityxe2x80x9d, i.e. what is termed a paraimmunity inducer, has been used therapeutically, metaphylactically and prophylactically in veterinary practice for a relatively long time. Paraimmunity inducers consist, for example, of chemically inactivated Parapoxvirus ovis, strain D 1701 (DE 3 504 940). BAYPAMUN(copyright) is a product which is prepared on the basis of this virus (Parapoxvirus ovis, strain D 1701).
In animals, the inactivated parapoxvirus induces nonspecific protection against infections caused by a very wide variety of pathogens. It is assumed that this protection is mediated by way of a variety of mechanisms forming part of the endogenous defence system.
These mechanisms include the induction of interferon, the activation of natural killer cells, the induction of xe2x80x9ccolony-stimulating activityxe2x80x9d (CSA), and the stimulation of lymphocyte proliferation. Earlier investigations into the mechanism of action demonstrated the stimulatory effect of interleukin 2 and interferonxcex13).
Against this background, the object therefore arises of further improving the therapeutic utility of the excellent effect of Parapoxvirus ovis so as to qualitatively increase the above-described generalized induction of a paraspecific immunoresponse by Parapoxvirus ovis, strain D 1701 and improve it such that better antiviral or anti-tumour effects can be achieved using lower doses. The therapeutic effect would then also be expected to have fewer side-effects.
The object of the invention was therefore to improve the immunological effect of Parapoxvirus. The object is achieved by using the abovementioned strains of Parapoxvirus ovis instead of the D1701 strain which is conventionally employed.
The present invention relates to the use of viruses which belong taxonomically to one of the Parapoxvirus ovis strains NZ2, NZ-7, NZ-10 or orf-11 for producing medicaments directed against viral infections and cancer in humans and animals.
The invention furthermore relates to the use of descendants of the strains according is to the invention, which descendants are obtained by passaging or adaptation to suitable cell systems, for example human cells, such as WI-38, MRC-5, monkey cells e.g. Vero cells, bovine cells such as BK-K13A47/Reg or MDBK, and ovine cells, such as MDOK, for producing medicaments against viral infections and cancer in humans and animals, and also relates to the use of parts or fragments of the said strains, and their passaging and adaptation variants, where parts are to be understood as being genomic or subgenomic fragments which are expressed with the aid of suitable vectors, such as vaccinia viruses, in suitable systems, such as fibroblast cell cultures and fragments are to be understood as being the fractions, which are obtained by biochemical purification, such as chromatography, of the expressed or physically disrupted viral particles, for producing medicaments which are directed against viral infections and cancer in humans and animals, and also relates to the use of one of the strains of Parapoxvirus ovis, and of derivatives which are derived as described above, for producing medicaments and pharmaceutical preparations as immunotherapeutic agents or immunoprophylactic agents for autoimmune diseases and for acute and chronic viral infections of the respiratory tract and the internal organs, and also relates to the use of one of the strains, and of derived derivatives, for producing medicaments and pharmaceutical preparations for stress metaphylaxis and for preventing or averting infectious diseases following stress and also in connection with infection prophylaxis within the context of operations and dental interventions, and also relates to the use of one of the strains, and of derived derivatives, for producing medicaments and pharmaceutical preparations for use in infection metaphylaxis or the therapy of acute and chronic viral infections, for example of the respiratory tract, of papilloma virus infections, of infection with viruses of the herpes group, of HIV infection, or of viral infection of internal organs, such as infection with hepatitis viruses, and also use in connection with diseases such as multiple sclerosis, asthma, warts and other neoformations of the skin, and also relates to the use of one of the strains, and of derived derivatives, for producing medicaments and pharmaceutical preparations for use on wounds, for accelerating wound healing processes, and use for supporting the healing of wounds which only heal poorly or which do not heal at all and ulcer of the leg, and also relates to the use of one of the strains, and of derived derivatives, for producing medicaments and pharmaceutical preparations for use for diseases of the spectrum of allergic diseases, psoriasis, neurodermatitis and other autoimmune diseases, such as lupus erythematodes, and also for improving wellbeing, for example in elderly patients, and also relates to the use of one of the strains, and of derived derivatives, for producing medicaments and pharmaceutical preparations for use against inflammatory, degenerative and proliferative diseases of the internal organs, for example Crohn""s diseases, of the skin, of the blood, of the central nervous system and its appended structures, and including the eye, including cancer, and also relates to the use of one of the strains, and of derived derivatives, in combination with other remedies for producing medicaments and pharmaceutical preparations for antiviral therapy or cancer therapy in humans and animals.
The invention preferably relates to the use of one of the strains of Parapoxvirus ovis in combination with other remedies for producing medicaments and pharmaceutical preparations for oral administration, and/or in a gastric juice-resistant formulation for oral administration.